The human transforming gene, dbl, was isolated from the DNA of a primary human diffuse B-cell lymphoma by the DNA transfection assay on NIH/3T3 cells, and cloned in cosmid vector as a human DNA sequence of 45 kilobases. An independent isolate of a dbl-related transforming gene was obtained following transfection of NIH/3T3 cells with DNA of a human nodular poorly differentiated lymphoma (NPDL). Physical mapping indicated that this transforming gene, designated NPDL-dbl, shared considerable homology with the prototype dbl oncogene. A cDNA library was constructed with polyadenylated RNA purified from a dbl third-cycle transfectant. The full size cDNA was isolated and completely sequenced. No homology was found by computer search of published nucleic acid and protein sequences. We have also cloned and sequenced the cDNA of the dbl proto- oncogene. Both cDNA clones were introduced into eukaryotic expression vectors and are being analyzed and compared for their transforming activity. Fifty percent of the DNAs of methylcholanthrene (MCA)-induced fibrosarcomas in mice were found to contain an activated K-ras gene. Analysis of cell lines established from the tumors for their growth capacity in vivo indicated that an activated K-ras gene was associated with a more malignant phenotype of the cells. Thymic lymphomas were induced in RFJ mice by percutaneous application of methylcholanthrene (MCA). DNAs from 83% of the tumors analyzed contained a transforming K-ras gene. The high frequency of K-ras activation in response to MCA seems to favor the concept that the activation of K-ras is related to the specificity of the mutagenic effect of MCA.